chr1-45500334-T-G
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_015506.3(MMACHC):c.2T>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000137 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MMACHC
NM_015506.3 start_lost
NM_015506.3 start_lost
Scores
8
5
3
Clinical Significance
Conservation
PhyloP100: 4.51
Genes affected
MMACHC (HGNC:24525): (metabolism of cobalamin associated C) The exact function of the protein encoded by this gene is not known, however, its C-terminal region shows similarity to TonB, a bacterial protein involved in energy transduction for cobalamin (vitamin B12) uptake. Hence, it is postulated that this protein may have a role in the binding and intracellular trafficking of cobalamin. Mutations in this gene are associated with methylmalonic aciduria and homocystinuria type cblC. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_015506.3 (MMACHC) was described as [Pathogenic] in ClinVar as 203823
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-45500334-T-G is Pathogenic according to our data. Variant chr1-45500334-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MMACHC | NM_015506.3 | c.2T>G | p.Met1? | start_lost | 1/4 | ENST00000401061.9 | |
MMACHC | NM_001330540.2 | c.-221T>G | 5_prime_UTR_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MMACHC | ENST00000401061.9 | c.2T>G | p.Met1? | start_lost | 1/4 | 2 | NM_015506.3 | P1 | |
MMACHC | ENST00000616135.1 | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461782Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727196
GnomAD4 exome
AF:
AC:
2
AN:
1461782
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Cov.:
30
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AC XY:
2
AN XY:
727196
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cobalamin C disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 557424). Disruption of the initiator codon has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595, 17768669, 19760748, 28693988). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the MMACHC mRNA. The next in-frame methionine is located at codon 58. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 24, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K4 (P = 0.0342);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at